From the California border, US 6 heads northeast through semi-desert Queen Valley with Boundary Peak (Nevada), Nevada's highest summit, and Montgomery Peak in California on the right. These twin peaks are the northernmost high summits of the White Mountains, both over 13,000 ft (4,000 m). The highway then climbs into the Pinyon-Juniper zone and crosses Montgomery Pass 7,167 ft (2,185 m).

Ely is the largest town on Route 6 in Nevada. US 50 joins Route 6 at Ely. East of Ely, Routes 6/50 cross the Schell Creek Range, known for verdant forests and meadows, and for a large deer and elk population. The highway descends to Spring Valley, then crosses the Snake Range at Sacramento Pass, north of Nevada's second-highest mountain, Wheeler Peak, where a branch road accesses Great Basin National Park. Beyond the pass, US 6 passes just north of Baker, a Mormon farming community, and reaches the Utah state line.

US 6 enters and leaves Utah concurrent with US 50. However, the two routes are different through the state. US 50 is the newer and shorter route. US 6 is the former route of US 50. US 6 forms an arch-shaped route with Spanish Fork at the apex.

US 6 is concurrent with Interstate 70 for a significant portion of its length from the Utah state line to Denver. Within the city limits, US 6 follows Denver's 6th Avenue (known as "6th Avenue Freeway"). The highway then travels north briefly, and follows Interstate 76 for most of its length east of Denver. It is unsigned while it is overlapped. The highest altitude along US 6 is 11,990 feet (3,650 m) at Loveland Pass, where it crosses the Continental Divide. It continues down Clear Creek Valley until it reaches I-70, where it is briefly overlapped until I-70 leaves Clear Creek Valley. US 6 continues down Clear Creek and into Denver, where it turns into a freeway with 6 lanes. East of Denver, it continues east while joined with I-76 until it reaches Sterling, where it diverges from the interstate. The last town in Colorado it passes is Holyoke.

From the Colorado state line, US 6 starts going southeast. The first town it goes into is Imperial. US 6 conjoins with US 34 near Culbertson, passing through McCook. US 6 then moves to the northeast, through Hastings. At Hastings, US 34 diverges and moves north. US 6 parallels Interstate 80 north of Milford until it reaches Lincoln. At Lincoln, US 6 becomes West "O" Street, then Cornhusker Highway and moves north of I-80 outside of the city, paralleling I-80 to Gretna. There US 6 moves due north and becomes the West Dodge Expressway and Dodge Street in Omaha. It passes through downtown Omaha on parallel one-way streets and runs concurrent with Interstate 480 in Omaha on its last Nebraska segment. East of Omaha, it crosses the Missouri River to enter Iowa at Council Bluffs, on a girder bridge completed in 1966 that replaced the Ak-Sar-Ben Bridge, which was the first road bridge to connect the two cities.

US 6 enters Iowa at Council Bluffs, across the Missouri River from Omaha where it intersects I‑29 within the first mile. Through Council Bluffs, it travels along Broadway and Kanesville Boulevard. Further east, the highway briefly overlaps US 59 near Oakland and continues east until Lewis. There, it turns sharply north-northeast to Atlantic where joins US 71 until I‑80. It overlaps I‑80 between US 71 and US 169 at De Soto. US 6 travels north with US 169 to Adel, then turns east to go toward Des Moines. It enters the Des Moines metro area along Hickman Road in Waukee and then forms the border between Urbandale to the north and Clive and Windsor Heights to the south. In Des Moines, Iowa Highway 28 joins US 6 at 63rd Street and the two routes head east and north on Merle Hay Road. US 6 splits away at Douglas Avenue and it continues east. Near the Des Moines River, Douglas Avenue becomes Euclid Avenue. In the northeastern part of the city, it intersects US 69 and I‑235. The highway turns onto Hubbell Avenue and heads into Altoona where it meets US and rejoins I‑80.[2]

In Illinois, US 6 parallels Interstates 74 and 80, mostly along its original routing, overlapping with I-74 for its first five miles (8.0 km) and I-80 for the final two miles (3.2 km) of its routing in Illinois. US 6 directly serves the downtowns of many cities for its length, including Oak Forest, Tinley Park, Moline, Geneseo, Atkinson, Annawan, Princeton, Peru, LaSalle, Ottawa, Channahon, and Joliet—unlike US 20, which, in Illinois, mainly consists of freeway sections that bypass the cities US 6 serves. Like nearby U.S. highways 30 and 52, US 6 skirts the Chicago city limits.

US 6 runs for 394 miles (634 km) in Pennsylvania between its entrance point 20 miles (32 km) west of Meadville and its exit at Matamoras. From the Ohio border to US 322 in Conneaut Lake, the route runs in a southeasterly direction. US 6 then joins US 322 and heads east to Meadville, picking up US 19 west of the city. South of downtown, US 322 splits from the concurrency while US 6 and US 19 remain concurrent through Meadville. The two routes continue northward to Mill Village, where US 6 and US 19 split at a junction with US 6N.

The 79-mile (127 km) portion of US 6 in New York is located primarily in Orange County, with lengthy stretches in Putnam and Westchester counties, and a small segment in Rockland County. The route enters the state along with US 209 in Port Jervis. The two routes split just north of town, with US 209 taking a more northerly route to access Kingston. US 6, in contrast, runs primarily east–west through southern New York.

On the other side of the river, US 6 and US 202 run along the Hudson to Peekskill, where the two routes split, allowing US 6 to continue to the northeast into Putnam County. In Brewster, US 6 meets US 202 once again. The routes become intertwined once more, running concurrent with one another into Connecticut.

US 6 runs for 116.3 miles (187.2 km) in Connecticut. It begins in the city of Danbury after crossing from New York, concurrent with US 202, and ends at the Rhode Island state line in the town of Killingly. In western Connecticut, US 6 either closely parallels or is concurrent with Interstate 84, serving as the local route in the suburbs of Danbury, Waterbury, Bristol, and Hartford. It crosses the Connecticut River (overlapped with I-84 and US 44) on the Bulkeley Bridge. In eastern Connecticut, US 6 is one of the principal routes connecting Hartford and Providence, R.I., passing through the small urban areas of Willimantic and Danielson. The unsigned portion of the Connecticut Turnpike then meets with US 6 shortly before crossing the Rhode Island state line.

U.S. 6 runs approximately 117.5 miles (189.1 km) in Massachusetts, paralleling I-195 between Providence and Wareham, and serves as the local business route. US 6 continues onto Cape Cod across the Sagamore Bridge as a freeway from Bourne to Orleans. North of Orleans, it becomes a surface road again to its terminus in Provincetown. Although the west-bound sign in Provincetown has been updated to reflect the shorter terminus in Bishop, California, the east-bound sign in Provincetown still reflects the original coast-to-coast terminus of Long Beach, California (see photo).

In New York, US 6 replaced all of Route 37—known as the "Bridge Route"—over the Bear Mountain Bridge, overlapped part of Route 17, and was assigned to an unnumbered road from Middletown west to Port Jervis.[10] The original route, which soon became US 6N, replaced Route 50, and is now part of U.S. Route 209. The part of US 6 in Pennsylvania replaced Route 7, also known as the Roosevelt Highway, an auto trail.[4] The Roosevelt Highway Association extended the name east with US 6 to Cape Cod by 1930.[11]

Most of US 32 and all of US 38 became a western extension of US 6 on June 8, 1931, and the Roosevelt Highway name followed.[12] To connect western Pennsylvania to central Indiana, relatively minor roads[4] (including the route for SR 6 in Indiana) were used, except west of Joliet, where it used a part of the old Detroit-Lincoln-Denver Highway. The short stub to Erie formed at the old west end became U.S. Route 6N, and US 32 remained in Illinois, running independently from Chicago to Princeton and overlapping US 6 to Davenport, Iowa.[8] US 32 has since been absorbed into U.S. Route 34.

Major William L. Anderson, Jr. of the U.S. Army recommended that US 6 be designated the Grand Army of the Republic Highway, honoring the Union soldiers in the Civil War. The Sons of Union Veterans of the Civil War began pushing for the name in April 1934. Massachusetts, the first state to apply the name, passed a law to do so on February 2, 1937; it was not until at least 1948 that all states had agreed. The highway was formally dedicated at the Long Beach end on May 3, 1953,[8] though the Roosevelt Highway Association continued to exist at least through the 1960s.[16]

Starting in the spring of 1983 U.S. 6 was a discontinuous route for almost one year, due to a massive landslide that destroyed the town of Thistle, Utah. The highway was rebuilt by blasting a path higher up the canyon wall. The landslide remains the most costly in the history of the United States.

Since the 1970s, portions of US 6 in Iowa have been moved permanently onto I-80. The first section, between US 71 and Adair, was rerouted in 1972.[18] In 1980, three lengthy sections were moved onto the Interstate: 26 miles (42 km) in western Iowa between Adair and Dexter,[19] 25 miles (40 km) in central Iowa between Altoona and Newton,[20] and 20 miles (32 km) in eastern Iowa between Wilton and Davenport.[21] On July 1, 2003, 15 miles (24 km) between Dexter and Adel were turned over to Dallas County.[22] US 6, which had previously split away from I-80 at the Dexter exit, was continued along I-80 to the US 169 interchange at De Soto, and then along US 169 to Adel.[23][24]

^Wellsboro Agitator, January 6, 1937: "The action taken at the recent San Francisco meeting of the American Association of State Highway Officials now gives it a single federal highway number from the Atlantic to the Pacific."